The invention relates to diagnostic, prognostic, and treatment methods for subjects suffering from kidney disease.
Chronic kidney disease (CKD) is estimated to affect 5-10% of adults in industrialized countries, such as the United States (Eknoyan et al., Kidney Int. 66:1310-4, 2004). Loss of renal function results in retention of excess water and metabolic wastes including urea. Intermittent hemodialysis (HD) is the mainstay of therapy for most patients with end-stage kidney disease (ESRD); however, mortality rates even after initiating HD remain distressingly high (de Jager et al., JAMA 302:1782-9, 2009). Attempts to optimize HD therapy by increasing patients' dose of dialysis have produced disappointing results in some instances (Eknoyan et al., N. Engl. J. Med. 347:2010-9, 2002), raising the question of whether effective clearance of soluble waste products is the only thing that these patients are lacking. Chronic uremia is associated with drastically increased cardiovascular risk (Lancet 2:1150-1, 1981). Individuals with CKD are 10-20 times likelier to die of cardiovascular causes than to survive long enough to require dialysis (Foley et al., Am. J. Kidney Dis. 32:S112-9, 1998). Proximate reasons for this association have been identified—accelerated atherosclerosis, hypertension, left ventricular hypertrophy—but the root causes linking CKD to cardiovascular disease (CVD) remain poorly understood (Lindner et al., N. Engl. J. Med. 290:697-701, 1974; Foley et al., Kidney Int. 47:186-92, 1995). Notably, the strongest and most validated pharmacologic means of modifying cardiovascular risk, cholesterol reduction with statins, does not appear to change outcomes in patients with ESRD (Wanner et al., N. Engl. J. Med. 353:238-48, 2005, Fellstrom et al., N. Engl. J. Med. 360:1395-407, 2009). This finding further suggests the existence of other mechanisms linking CKD to CVD (Karumanchi et al., Nat. Med. 16:38-40, 2010).
The clinical significance of chronically elevated urea concentrations in ESRD subjects remains controversial. Past studies have shown that average blood urea nitrogen (BUN) levels are not reliable predictors of mortality in CKD patients (Johnson et al., Mayo Clin. Proc. 47:21-9, 1972; Chertow et al., Kidney Int. 56:1872-8, 1999; Stosovic et al., Ren. Fail. 31:335-40, 2009), and although intermittent hemodialysis significantly reduces patients' average blood urea levels, the HEMO study found that increasing the dose of hemodialysis (as evidenced by increased equilibrated Kt/V) conferred no measurable survival benefit to these patients (Eknoyan et al., N. Engl. J. Med. 347:2010-9, 2002).
Thus, there is a need for improved diagnostic and prognostic methods for patients suffering from kidney disease, as well as methods for treating such patients.